Albert Rizvanov: ‘We joined the race for the vaccine late’

Types of vaccines: classic of the genre and state-of-the-art developments

Mr Rizvanov, let’s start from afar: what are today’s tendencies for vaccine development? What is the news? What are numerous groups creating the coronavirus vaccine working with?

There are several types of vaccines. Some have been applied for centenaries, some — for decades, and there are also very new developments based on gene therapy. The classic case is the use of weakened or killed pathogen of a disease. Such technologies were used at the dawn of vaccination. A more “natural” effect and availability of production technologies are the advantages of such vaccines. As for the disadvantages, firstly, it is a long process of production of such medicine. Secondly, these vaccines can contain different impurities that can theoretically have additional side effects.

However, is the immune response to them good?

An immune response to a weakened vaccine will be great, it’s what we need because a vaccine virus, in fact, causes a mild disease case. But if a person has weak immunity, such medicine can have a strong side effect — here it is a matter of balance between safety and effectiveness. This is why scientists began to look for options to make a safer vaccine.

When biotechnology developed so much that humans learnt how to obtain separate proteins, of course, the creation of vaccines became one of the first areas where biotechnology began to be applied. Now genes of pathogens can be placed in microorganisms or eukaryotic cells, and big amounts of purified protein antigen can be received (it causes an immune response — antibodies are created for an antigen). The upside of such methods is a purer vaccine and forecasted immune response.

What are the downsides?

Firstly, it takes much time to set up production. Secondly, only one of the virus proteins stimulate an immune response — in this case, it is hard to obtain an integrated immune response. The most immunogenic virus protein, which causes the strongest immune response, is usually chosen, which partly compensates for this disadvantage. Several proteins can be used in combination, but this significantly complicates and raises the price of the process of creation and production of the vaccine.

When biotechnology developed so much that humans learnt how to obtain separate proteins, of course, the creation of vaccines became one of the first areas where biotechnology began to be applied

Is it the most pathogenic protein?

Not necessarily. It is usually a protein that makes sure that the virus is linked with a cell and goes in. There are a lot of types of such vaccines, for instance, when not whole virus proteins but their fragments (peptides) that cause also cause immune response are produced and introduced to the human organism. But here the duration of the development of such vaccines, their costliness and limited effectiveness become an issue. This is why long-term research is necessary to choose correct proteins, their correct fragments so that they will cause the most effective immune response of the organism.

What’s the novelty of the developments?

Gene therapeutic vaccines are one of the modern areas when not the pathogen itself and not its protein is injected but genetic information that codes it. When it gets to the human organism, such a genetic programme lead to the synthesis of proteins of the virus. The immune system recognises these strange proteins and reacts to them. To draw an analogy, a usual vaccine is like a person who is given fish as food. While a genetically engineered vaccine is a fishing rod he catches this fish with. In other words, the organism itself learns how to produce strange proteins it is learning to fight. The advantage of such vaccines is the speed of development. It can be done immediately after the pathogen’s genome is deciphered.

Like it happened to the coronavirus when the genetic sequence had already been known by March?

This coronavirus’s genome was deciphered as early as late 2019. We joined this race for the vaccine late. So when the pathogen’s genome is known, a prototype of the vaccine can be obtained in the laboratory in a month, and its action can start to be tested.

“Single-use magic wand”: what’s wrong with the Gamaleya Institute’s vaccine

What problems do gene therapeutic vaccines have?

Now there are several types of gene therapeutic vaccines. A DNA vaccine is one of the simplest, we used this technology as foundation for our first medicine. It is when the virus gene (or two genes in our case) is built in the circular DNA molecule. If it is placed in the cell (usually it is an intramuscular injection), the cell processes the information and starts to produce virus proteins. The advantage of such a vaccine is the speed and safety. In general it is the safest gene therapeutic platform. The disadvantage is its frequent low effectiveness. In fact, this is what we are finding out now with our first vaccine. But it isn’t a failure, it is a valuable experience that will allow us to understand better how the organism reacts to the new coronavirus infection.

This is why we switched to the second version. To compensate for the lack of effectiveness, scientists sometimes use vectors to deliver genes of the pathogen to the cell — they are built in another safe virus that penetrates the organism and serves as kind of “courier”. The Gamaleya Institute, for instance, chose such an approach that promises to produce the end substance soon.

The Gamaleya Institute is using two injections based on different adenoviruses hoping that humans still don’t have immunity to at least one of them. It is the so-called dual-vector vaccine

They are using the adenovirus.

Yes, they are using the adenovirus vector that has the coronavirus gene built in it. We are using the same technology in the second version of our vaccine, the case is that we are building the coronavirus gene in the adeno-associated virus.

Is this virus dangerous for humans?

Adenoviruses make people sick. But the one used as a vector is deliberately weakened and can’t cause any diseases in people — it can’t proliferate in the human organism. It just serves as a courier.

But the adenovirus has a big disadvantage as well: as pathogens are its “relatives”, as I already said, it means many already have immunity to it. And this can seriously reduce the effectiveness of the medicine — the organism simply won’t let such a “courier” in, the immune system will catch it at the gates. Or injection of the medicine can cause a strong immune reaction, like an allergy.

This is why the same Gamaleya Institute is using two injections based on different adenoviruses hoping that humans yet don’t have immunity to at least one of them. It is the so-called dual-vector vaccine.

Does it mean the problem has been solved?

Not really. Even if this vaccine works, it can’t be used in the future for a booster dose. The organism will have immunity to this “courier”. This is why if we assume that immunity will work for a year, another virus vector (“courier”) will have to be found for the vaccine next year. So it is a single-use magic wand.

This is why you have a problem with the second version of your vaccine, right?

Not exactly. The adeno-associated virus we are using as a vector doesn’t make people sick. It means it causes a much weaker immune response. This allows using such a vector more than once.

Are there any other platforms to develop vaccines?

There is another area in gene therapeutic vaccine when not DNA and the virus but messenger RNA (“instruction” a cell uses for DNA synthesis) is delivered to the organism. It needs additional reagents or nano-particles to make sure RNA gets to the cell.

Such developments are made in different countries, and the effectiveness of such a platform for developing a vaccine against the coronavirus was proved. So now there are a lot of different technological platforms, they are tested to choose the most effective, safest and longest.

So even if all developed vaccines are permitted right now, there will not certainly be enough production capacities in the short run

“We haven’t heard any proposals for support from the state”

There are hundreds of developers around the world. Many promise they are about to start producing ready-to-use vaccines. Does it mean we will be able to be vaccinated against the coronavirus soon?

I don’t think so. Even if certification can be accelerated, it isn’t certain if companies will be able to produce enough vaccines.

Our producers that are giving the mass media interviews, they all are merrily reporting they will already launch the production this year. But if we have a look at the amount they are ready to make — it is millions a year. While Russia’s population is 140 million!

Even the biggest producers in the world — such as Pfizer — are ready to make, for instance, tens of millions of doses a year. A year, not a month. You understand that this won’t meet the needs of America alone. As for Europe, the rest of the world... So even if all developed vaccines are permitted right now, there will not certainly be enough production capacities in the short run.

You are already working on the second type of the vaccine at the Kazan university, you say the first one wasn’t proved effective enough. How is its development doing?

We already have a prototype, now we need to have big amounts of it to test on animals.

What will happen next? Clinical research and accelerated certification?

Unfortunately, we don’t have money to continue the research. We will likely perform tests on animals, but we don’t have financing on further work. Information that all problems are about to be solved began to appear in the mass media. And potential investors suddenly lose their interest. A commercial interest is lost because it feels like all cream has already been skimmed.

So now you will test the second version on mice, and if the research is crowned with success, what will happen next?

It is hard to say now. We will need to consider the results we will obtain. But we should understand that not the final result but the process itself is important for us. Firstly, we are anyway a university, and our mission is to develop science and education. It is the projects in which our students and postgraduates, young scientists are familiarising with the latest technologies. Secondly, it is obviously not the last pandemic, unfortunately. It means in the future we will be ready for new challenges by accumulating experience now. After all, if there are problems with the first certified vaccines, we will have an alternative on the bench of substitutes.

If there are problems with the first certified vaccines, we will have an alternative on the bench of substitutes

Does it mean that now you will go through certain obstacles, and if something serious happens in the future, you will already understand what to start with and how to do it?

Yes, it is a baptism of fire for us.

So can’t we say that our Kazan vaccine that will be produced on a large scale will appear soon?

No, I am afraid. We informed both the Ministry of Science and Ministry of Industry and Trade, they collect information about developers of vaccines and test systems every week. But all this goes to Moscow as extras. We haven’t heard any proposals for support from the state.

“There is a big fight between the three agencies”

Anna Popova reports on the development of 36 coronavirus vaccines in Russia now. Are they the extras?

A handful is really working. There are three key players — the Gamaleya Institute (the Ministry of Health), Vektor (Russia’s consumer rights protection watchdog Rospotrebnadzor) and the Institute of Vaccines and Serum in Saint Petersburg (the Federal Medical and Biological Agency). It is a very competitive market. There is a big fight between the three agencies, and all this business has already been divided between these big players.

The state bet on these three developers, the rest is left to their own devices and are working only on their own initiative.

But you are saying yourself that none of them can provide necessary production capacities. What will they do next? Will they sell their technology, expand it to a bigger pharmaceutical company? How will this problem be solved?

Outsourcing is an option. It can be ordered in India and China. There are pharmaceutical companies there that are ready to establish production on a basis of contracts.

Will it be cheaper than setting up production here in Russia?

Unfortunately, any import substitution in Russia is less competitive than a business with China, India and even America sometimes from a financial perspective.

What about the test systems you developed?

Now we are submitting applications to register the test systems, we are completing the development of test strip technology. Here we already have corporate clients, and the test system is anyway isn’t medicine. It is easier to certify, and investments are much smaller there. This is why here we are fully financed and now we are preparing documents to obtain a certificate.

So, all in all, you began developing a vaccine following one road, then you understood that it was fast and safe but ineffective enough. Then you switched to another type of the vaccine. When approximately are you going to switch from the ready prototype to testing on mice?

There is no race now. The project is becoming more technological, scientific, and I think that we will launch the testing of the second version of the vaccine on animals in September.

The project is becoming more technological, scientific, and I think that we will launch the testing of the second version of the vaccine on animals in September

Then the development becomes a subject of scientific research and educational technology. Will you attract students to this work?

Yes, of course. It is students, candidates for a master’s degree, postgraduates. We get patents, prepare research papers. We create competencies to be able to use them in the future if needed. We create a scientific and technological platform in Tatarstan that will allow working effectively in the future.